Gene therapy promises to be a singular advance in the treatment of both acquired and genetic diseases at the most fundamental levels of pathology. Hemophilia B patients express insufficient levels of factor IX. This protein is normally expressed in the liver. Current methods of gene delivery to the liver are not very efficient and results in short term expression. Yet, serum proteins such as factor IX can be produced at ectopic sites and secreted to the serum. A novel method of intravascular injection of plasmid DNA expression vectors results in highly efficient transfection of skeletal muscle. This project will use this simple and innovative approach to develop a gene therapy protocol for the treatment of hemophilia B. In this Phase I application, experiments are proposed to optimize expression of human factor IX in rats following intravascular delivery of plasmid DNA expression vectors. During the Phase II studies, this gene therapy protocol will be tested in a canine hemophilia B model. These experiments will generate the pre-clinical data required for a human trial application. The intravascular delivery methodology also will be used in Phase III for the internal development of gene therapy protocols for applications such as other clotting factor abnormalities, phenylketonuria, alpha1-antitrypsin deficiency, complement factor deficiencies, and other hematologic or metabolic disorders within Mirus and licensed to other companies for use within their gene therapy applications. PROPOSED COMMERCIAL APPLICATIONS: Vectors and methodology developed under this proposal should enable a gene therapy protocol for hemophilia B.